A “Hot Spring” Mimetic Aerogel Loaded with Multiple Amino Acids Modulates the Chronic Inflammatory Microenvironment Through Metabolic Reprogramming

ABSTRACT Chronic wounds, such as diabetic foot ulcers, often exhibit lower temperatures due to impaired local circulation, leading to reduced cellular metabolism and delayed healing. This study explores a new strategy to accelerate wound healing by enhancing the cell metabolism of essential amino acids through a “hot spring” mimetic photothermal effect. We engineered an extracellular matrix mimetic nanofiber aerogel co‐delivering an eight essential‐amino‐acid cocktail and photothermally active SrCuSi4O ₁₀ bioceramic particles to support chronic wound repair. In vitro, fibroblasts cultured at 25°C versus 37°C showed that physiological temperature preserved the pro‐healing bioactivity of the amino‐acid treatment with minimal cytotoxicity and was associated with enhanced glutathione redox metabolism. In vivo, the amino acid–loaded aerogel combined with SrCuSi ₄ O ₁₀ ‐mediated photothermal therapy accelerated wound closure and improved regenerative outcomes, including increased cellular proliferation, collagen deposition, and neovascularization. Immunohistochemical analysis showed a reduction in neutrophil infiltration, M1 macrophage polarization, and pro‐inflammatory cytokines, while increasing M2 macrophage polarization and anti‐inflammatory cytokine production, thus shifting the local inflammatory response from pro‐inflammatory to regenerative. This approach demonstrates potential as an effective therapeutic option for enhancing the healing of chronic wounds.